A process for the preparation of 2-chloro-3-alkoxymethyl-4-methanesulfonylbenzoic acids

Abstract

This invention relates to a method for preparing 2-chloro-3-alkoxymethyl-4-methanesulfonylbenzoic acid. The method includes the following steps: methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate undergoes esterification in a tertiary alcohol solvent in the presence of an alkaline substance to obtain 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate; 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate is then reacted with an alcohol in the presence of an alkaline substance, or the 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate is reacted with an alkali metal alkoxide to obtain the 2-chloro-3-alkoxymethyl-4-methanesulfonylbenzoic acid. The preparation method provided by this invention uses a tertiary alcohol as a solvent, and the raw material undergoes esterification in the presence of an alkaline substance, reducing the content of impurities and significantly improving the yield and quality of the target compound, thus ensuring the final synthesis of high-quality cyclosulfonone and furazolidone technical.

Description

Technical Field

[0001] This invention belongs to the field of fine chemical intermediate synthesis, and relates to a method for preparing 2-chloro-3-alkoxymethyl-4-methanesulfonylbenzoic acid, specifically to a method for preparing 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid and 2-chloro-3-[(RS)-tetrahydrofuran-2-ylmethoxymethyl]-4-methanesulfonylbenzoic acid. Background Technology

[0002] 4-Hydroxyphenylpyruvate dioxygenase (HPPD) is one of the most important herbicide targets. HPPD inhibitor herbicides hold a significant position among the 18 classes of herbicides globally, accounting for 5.8% of the global herbicide market. These herbicides are known for their broad spectrum, high efficiency, and slow resistance development. HPPD inhibitor herbicides share a similar mechanism of action but are not entirely structurally related, and include triketones, pyrazolones, and isoxazolones. Tembotrione and tefructoxyn are HPPD triketone herbicides, with the following structural formulas:

[0003]

[0004] Cyclosulfonyl was independently developed by Bayer in 2007. It exhibits higher activity than mesotrione, is safer for crops, and is primarily used for weed control in corn fields, possessing a broad spectrum of herbicides. Furazolidone was jointly developed by Bayer, HOKKO (Japan's Hokko Group), and Zen-Noh (an international trading company operated by the Japan Agricultural Cooperatives), and was launched in Japan in 2008. Furazolidone is mainly used for weed control in rice paddies. Cyclosulfonyl's compound annual growth rate (CAGR) reached 51.6% between 2009 and 2014, while furazolidone's CAGR was 20.1% during the same period. Furthermore, the patents for both herbicides will expire in September 2019, at which point a new round of development opportunities is expected.

[0005] Compound 2-chloro-3-alkoxymethyl-4-methanesulfonylbenzoic acid is a key intermediate in this series of compounds, and its structural formula is as follows:

[0006]

[0007] CN105601548A, CN104292137A, US6376429, CN1364160A, and CN1323292A all disclose a method for preparing the target methyl ester from methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate under alkaline conditions by reacting it with the corresponding alcohol or directly with the corresponding sodium alkoxide, and then further saponifying it to prepare 2-chloro-3-alkoxymethyl-4-methanesulfonylbenzoic acid. The reaction formula is as follows:

[0008]

[0009] Where R is trifluoroethyl, it is a cyclosulfonone intermediate; where R is 2-tetrahydrofuranmethyl, it is a furazolidone intermediate.

[0010] Although the above method can yield the target compound, the resulting product has poor purity, with a significant proportion of the impurity 2-chloro-3-methoxymethyl-4-methanesulfonylbenzoic acid. The proportion of this impurity varies considerably depending on the substrate; when R is trifluoroethyl, the normalization ratio is approximately 3–5%, while when R is 2-tetrahydrofuranmethyl, the normalization ratio can reach 8–12%. This impurity is generated by methanol as a byproduct due to ester-base breakage or transesterification in the raw material under alkaline conditions. The methanol further reacts with the benzyl bromide group in the raw material. Because this impurity has a similar structure and properties to the target compound, it is difficult to remove and is carried into subsequent reactions, giving rise to corresponding new impurities. Ultimately, this severely affects the quality of the cyclosulfonone and furazolidone technical grade products.

[0011] With the improvement of my country's pesticide management system and its alignment with international standards, higher requirements have been placed on the quality of pesticide products. Relevant laws and regulations have also been introduced to manage pesticide impurities. Therefore, research on the mechanisms of impurity formation and control methods is particularly important. To obtain high-quality cyclosulfonyl and furazolidone technical grade pesticides, a new method for preparing 2-chloro-3-alkoxymethyl-4-methanesulfonylbenzoic acid is urgently needed to reduce impurity content and improve the purity of the target product. Summary of the Invention

[0012] To address the aforementioned technical problems, this invention provides a method for preparing 2-chloro-3-alkoxymethyl-4-methanesulfonylbenzoic acid, which effectively avoids the generation of the impurity 2-chloro-3-methoxymethyl-4-methanesulfonylbenzoic acid, thus ensuring the subsequent preparation of high-quality cyclosulfonone and furazolidone technical materials.

[0013] To achieve this objective, the present invention adopts the following technical solution:

[0014] A method for preparing 2-chloro-3-alkoxymethyl-4-methanesulfonylbenzoic acid includes the following steps:

[0015] (1) Methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate was subjected to esterification in a tertiary alcohol solvent in the presence of an alkaline substance to obtain 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate;

[0016] The reaction process described in this step can be represented by the following reaction equation:

[0017]

[0018] In the formula, M represents an alkali metal.

[0019] (2) 2-Chloro-3-bromomethyl-4-methanesulfonylbenzoate is reacted with an alcohol in the presence of an alkaline substance or 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate is reacted with an alkali metal alkoxide to obtain the 2-chloro-3-alkoxymethyl-4-methanesulfonylbenzoic acid.

[0020] The reaction process described in this step can be represented by the following reaction equation:

[0021]

[0022] In the formula, M represents an alkali metal, and R represents 2,2,2-trifluoroethyl or 2-tetrahydrofuranmethyl.

[0023] The method described above involves breaking the ester bonds of the starting material under alkaline conditions during the esterification process, removing the methoxy group from the molecule to obtain 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate. This salt further undergoes a condensation reaction with the corresponding alcohol or sodium alkoxide to prepare the target compound. This method removes the methoxy group before etherification, effectively avoiding the generation of the impurity 2-chloro-3-methoxymethyl-4-methanesulfonylbenzoate in the subsequent etherification reaction, thus significantly improving the yield and quality of the target compound.

[0024] Alkaline hydrolysis of esters is a conventional reaction. However, the molecular structure of methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate used in this invention contains a benzyl bromide group that is highly sensitive to alkali. Conventional ester hydrolysis methods are not feasible in this invention. The benzyl bromide group will participate in the reaction to generate a large amount of benzyl alcohol and dibenzyl ether compounds, with the following structural formula:

[0025]

[0026] This invention involves carrying out the reaction in a special solvent system, namely a tertiary alcohol solvent, which can effectively reduce the activity of benzyl bromide and result in high purity of the product from the alkaline hydrolysis step.

[0027] As a preferred technical solution of the present invention, the tertiary alcohol in step (1) is any one or a combination of at least two of tert-butanol, tert-pentanol or 2-methyl-2-pentanol, preferably tert-butanol.

[0028] Preferably, in step (1), the amount of the tertiary alcohol solvent used relative to 1 mol of methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate is 700 to 3500 mL, for example, 700 mL, 1000 mL, 1500 mL, 2000 mL, 2500 mL, 3000 mL or 3500 mL.

[0029] As a preferred technical solution of the present invention, the molar ratio of the raw material to the alkaline substance in step (1) is 1:(1 to 1.1), for example, it can be 1:1, 1:1.02, 1:1.05, 1:1.08 or 1:1.1.

[0030] Preferably, the alkaline substance in step (1) is any one of sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, potassium hydride, metallic sodium or metallic potassium, preferably sodium hydroxide.

[0031] Preferably, the sodium hydroxide is first prepared into an aqueous solution with a mass concentration of 30% to 96%, for example, 30%, 40%, 50%, 60%, 70%, 85%, or 96%.

[0032] Preferably, the potassium hydroxide is first prepared into an aqueous solution of sodium hydroxide, and the mass concentration of potassium hydroxide is 30% to 96%, for example, 30%, 40%, 50%, 60%, 70%, 85% or 96%.

[0033] As a preferred technical solution of the present invention, the temperature of the esterification reaction in step (1) is 25 to 40°C, for example, it can be 25°C, 30°C, 35°C or 40°C.

[0034] Preferably, the esterification reaction time in step (1) is 5 to 12 hours, for example, 5 hours, 8 hours, 10 hours or 12 hours.

[0035] As a preferred technical solution of the present invention, the alcohol in step (2) is 2,2,2-trifluoroethanol or 2-tetrahydrofuran methanol.

[0036] Preferably, in step (2), the molar ratio of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate to alcohol is 1:(1.05 to 1.35), for example, it can be 1:1.05, 1:1.15, 1:1.25 or 1:1.35.

[0037] As a preferred technical solution of the present invention, the alkaline substance in step (2) is any one of sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, and potassium hydride.

[0038] Preferably, the sodium hydroxide is first prepared into an aqueous solution with a mass concentration of 30% to 96%, for example, 30%, 40%, 50%, 60%, 70%, 85%, or 96%.

[0039] Preferably, the potassium hydroxide is first prepared into an aqueous solution of sodium hydroxide, and the mass concentration of potassium hydroxide is 30% to 96%, for example, 30%, 40%, 50%, 60%, 70%, 85% or 96%.

[0040] Preferably, the molar ratio of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate to the alkaline substance in step (2) is 1:(1.2 to 1.5), for example, it can be 1:1.2, 1:1.3, 1:1.4 or 1:1.5.

[0041] As a preferred technical solution of the present invention, the molar ratio of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate to alkali metal alkoxide in step (2) is 1:(1.2 to 1.5), for example, it can be 1:1.2, 1:1.3, 1:1.4 or 1:1.5.

[0042] Preferably, the alkali metal alkoxide in step (2) is obtained by reacting an alcohol with an alkali metal.

[0043] Preferably, the alkali metal is sodium or potassium.

[0044] In this invention, when the 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate described in step (2) reacts with an alcohol in the presence of an alkaline substance, the order of addition is as follows: first, the alkaline substance and the alcohol are added to the reaction solvent, and then the 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate is added.

[0045] In this invention, the order of adding 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate to react with alkali metal alkoxide in step (2) is to first put the alkali metal alkoxide into the solvent, and then add the 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate.

[0046] In this invention, the order of adding materials in step (2) cannot be changed. If 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate is first placed in the solvent and a mixture of alkaline substance and alcohol is added dropwise or sodium alkoxide or potassium alkoxide is added dropwise to react, the benzyl alcohol impurities and double-connected impurities will increase significantly.

[0047] As a preferred technical solution of the present invention, the solvent used in step (2) is any one or a combination of at least two of acetonitrile, DMF, DMSO or THF.

[0048] Preferably, in step (2), the amount of solvent used relative to 1 mol of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate is 700 to 3500 mL, for example, 700 mL, 1000 mL, 1500 mL, 2000 mL, 2500 mL, 3000 mL or 3500 mL.

[0049] As a preferred technical solution of the present invention, the reaction temperature in step (2) is -5 to 15°C, for example, it can be -5°C, 0°C, 5°C, 10°C or 15°C.

[0050] Preferably, the 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate in step (2) is added to the reaction system in step (2) in batches, and the total feeding time of the 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate is 1 to 3 hours, for example, 1 hour, 1.5 hours, 2 hours, 2.5 hours or 3 hours;

[0051] Preferably, the reaction time in step (2) is 3 to 6 hours, for example, 3 hours, 4 hours, 5 hours or 6 hours.

[0052] Preferably, after the reaction in step (2) is completed, acidification is performed to obtain the 2-chloro-3-alkoxymethyl-4-methanesulfonylbenzoic acid.

[0053] Preferably, the acid used for acidification is hydrochloric acid.

[0054] Preferably, the pH value of the acidified reaction system is 2 to 3, for example, it can be 2, 2.1, 2.3, 2.4, 2.5, 2.7 or 3.

[0055] As a preferred embodiment of the present invention, the preparation method includes the following steps:

[0056] (1) Methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate is subjected to esterification in a tertiary alcohol solvent in the presence of an alkaline substance for 5-12 h at 25-40 °C to obtain 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate. The amount of the tertiary alcohol solvent used is 700-3500 mL relative to 1 mol of the raw material, and the molar ratio of the raw material to the alkaline substance is 1:(1-1.1).

[0057] (2) 2-Chloro-3-bromomethyl-4-methanesulfonylbenzoate is reacted with an alcohol in the presence of an alkaline substance, wherein the molar ratio of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate to alcohol is 1:(1.05-1.35) and the molar ratio of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate to alkaline substance is 1:(1.2-1.5), or 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate is reacted with an alkali metal alkoxide, wherein the molar ratio of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate to alkali metal alkoxide is 1:(1.2-1.5), the reaction time is 3-6 h, the reaction temperature is -5-15 °C, and the 2-chloro-3-alkoxymethyl-4-methanesulfonylbenzoic acid is obtained after solvent removal, water dilution, acidification, filtration and drying.

[0058] The numerical range described in this invention includes not only the point values ​​listed above, but also any point values ​​within the numerical ranges not listed above. Due to space limitations and for the sake of brevity, this invention will not exhaustively list all the specific point values ​​included in the range.

[0059] Compared with the prior art, the present invention has at least the following beneficial effects:

[0060] This invention uses a tertiary alcohol as a solvent, and the raw material undergoes an esterification reaction in the presence of an alkaline substance to remove the methoxy group from the molecular structure. This avoids the generation of 2-chloro-3-methoxymethyl-4-methanesulfonylbenzoic acid, a major impurity present in existing technologies, and fundamentally improves the quality of the intermediate and the yield of the reaction. The normalization ratio of the product 2-chloro-3-bromomethyl-4-methanesulfonylbenzoic acid in liquid chromatography can reach up to 98.3%.

[0061] 2-Chloro-3-bromomethyl-4-methanesulfonylbenzoate is further subjected to an etherification reaction to generate the target compound. The two-step reaction of this method can achieve a maximum yield of 93.8% and a maximum content of 98.7% as detected by HPLC. The yield and quality of the target compound are greatly improved, which provides a guarantee for the final synthesis of high-quality cyclosulfonone and furazolidone technical. Detailed Implementation

[0062] To facilitate understanding of the present invention, the following embodiments are provided. Those skilled in the art should understand that these embodiments are merely illustrative and should not be construed as limiting the scope of the invention.

[0063] The preparation of methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate can be performed according to the methods described in CN105601548, CN104292137, US6376429, CN1146548, or CN1323292. In the following examples, the preparation method of methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate is based on the method provided in CN105601548. The purity of the prepared methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate was determined to be 98% by HPLC.

[0064] Example 1

[0065] (1) The preparation of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate can be represented by the following reaction equation:

[0066]

[0067] Add 200 mL of tert-butanol to the reaction flask and start stirring. Add 8.8 g of sodium hydroxide (48%, 0.105 mol) dropwise at room temperature. After the sodium hydroxide is evenly dispersed, maintain the reactor temperature at 25°C. Add 34.8 g of methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (98%, 0.1 mol) to the reactor for alkaline hydrolysis. The reaction is slightly exothermic; maintain the reactor temperature at 25°C and react for 7 hours. After the reaction is complete, the normalized content of sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate is 98.2% as shown in the liquid chromatography. The solvent is removed under negative pressure and the sodium salt is directly used for subsequent etherification reactions.

[0068] (2) The preparation of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid can be represented by the following reaction equation:

[0069]

[0070] Add 50 mL of trifluoroethanol to the reaction vessel, start stirring, add 5.2 g of sodium hydride (60%, 0.13 mol) at room temperature, stir until completely dissolved, and obtain sodium trifluoroethanol alkoxide solid after solvent removal, and seal for later use.

[0071] 200 mL of THF was added to sodium trifluoroethanol, stirred and dissolved, and the temperature of the reactor was controlled at 5 °C. Sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (98.2%, 0.1 mol) prepared in step (1) was added to the reaction flask in eight portions, with a total addition time of 3 h. After addition, the reaction was kept at the temperature for 3 h. After the reaction was completed, the product was desolvated under negative pressure. 120 mL of water was added to the reactor residue, stirred and dissolved, and concentrated hydrochloric acid was added dropwise to acidify the pH of the system to 2. After filtration, rinsing with water, and drying, 32.9 g of product was obtained. HPLC quantification showed that the content of the target compound 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid was 98.7%, and the yield of the two-step reaction was 93.8% based on methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate.

[0072] Example 2

[0073] (1) The preparation of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate can be represented by the following reaction equation:

[0074]

[0075] Add 200 mL of tert-amyl alcohol to the reaction flask and start stirring. Add 8.8 g of sodium hydroxide (48%, 0.105 mol) dropwise at room temperature. After the sodium hydroxide is evenly dispersed, maintain the reactor temperature at 25°C. Add 34.8 g of methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (98%, 0.1 mol) to the reactor for alkaline hydrolysis. The reaction is slightly exothermic. Maintain the reactor temperature at 25°C and react for 7 hours. After the reaction is complete, the normalized content of sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate is 97.8% as shown in the liquid chromatography. The solvent is removed under negative pressure and the solution is directly used for subsequent etherification reactions.

[0076] (2) The preparation of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid can be represented by the following reaction equation:

[0077]

[0078] Add 50 mL of trifluoroethanol to the reaction vessel, start stirring, add 2.8 g of metallic sodium (99%, 0.12 mol) at room temperature, stir until completely dissolved, and obtain sodium trifluoroethanol alkoxide solid after solvent removal, and seal for later use.

[0079] 70 mL of DMSO was added to sodium trifluoroethanol, stirred and dissolved, and the temperature of the reactor was controlled at -5 °C. Sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (97.8%, 0.1 mol) prepared in step (1) was added to the reaction flask in eight portions, with a total addition time of 2 h. After addition, the reaction was kept at the temperature for 5 h. After the reaction was completed, the solution was removed under negative pressure, and 120 mL of water was added to the reactor residue. After stirring and dissolving, concentrated hydrochloric acid was added dropwise to acidify the pH of the system to 2. After filtration, rinsing with water, and drying, 33.3 g of product was obtained. HPLC quantification showed that the content of the target compound 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid was 96.7%, and the yield of the two-step reaction was 92.4% based on methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate.

[0080] Example 3

[0081] (1) The preparation of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate can be represented by the following reaction equation:

[0082]

[0083] Add 70 mL of tert-butanol to the reaction flask and start stirring. Add 14 g of sodium hydroxide (30%, 0.105 mol) dropwise at room temperature. After the sodium hydroxide is evenly dispersed, maintain the reactor temperature at 30 °C. Add 34.8 g of methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (98%, 0.1 mol) to the reactor for alkaline hydrolysis. The reaction is slightly exothermic; maintain the reactor temperature at 30 °C and react for 12 h. After the reaction is complete, the normalized content of sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate is 92.5% as shown in the liquid chromatography. The solvent is removed under negative pressure and the sodium salt is directly used for subsequent etherification reactions.

[0084] (2) The preparation of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid can be represented by the following reaction equation:

[0085]

[0086] Add 160 mL of LDM, 11.6 g of trifluoroethanol (99%, 0.115 mol), and 17.3 g of sodium hydroxide solution (30%, 0.13 mol) to the reaction vessel, start stirring, and control the temperature of the vessel at 5 °C. Add the sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (92.5%, 0.1 mol) prepared in step (1) to the reaction flask in eight portions, with a total addition time of 2 h. After addition, keep the reaction vessel warm for 4 h. After the reaction was complete, the solvent was removed under negative pressure. 120 mL of water was added to the residue in the reactor, and after stirring to dissolve, concentrated hydrochloric acid was added dropwise to acidify the pH of the system to 3. After filtration, washing with water, and drying, 30.7 g of product was obtained. HPLC quantification showed that the target compound 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid had a content of 95.8%, and the two-step reaction yield was 84.4% based on methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate.

[0087] Example 4

[0088] (1) The preparation of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate can be represented by the following reaction equation:

[0089]

[0090] Add 200 mL of tert-butanol to the reaction flask and start stirring. Add 4.6 g of sodium hydroxide (96%, 0.11 mol) dropwise at room temperature. After the sodium hydroxide is evenly dispersed, maintain the reactor temperature at 40 °C. Add 34.8 g of methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (98%, 0.1 mol) to the reactor for alkaline hydrolysis. The reaction is slightly exothermic. Maintain the reactor temperature at 40 °C and react for 5 hours. After the reaction is complete, the normalized content of sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate is 96.4% as shown in the liquid chromatography. The solvent is removed under negative pressure and the sodium salt is directly used for subsequent etherification reactions.

[0091] (2) The preparation of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid can be represented by the following reaction equation:

[0092]

[0093] Add 130 mL of DMF, 10.6 g of trifluoroethanol (99%, 0.105 mol), and 14.1 g of potassium tert-butoxide (95%, 0.12 mol) to the reaction vessel, start stirring, and control the temperature of the vessel at 10 °C. Add the sodium salt of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (96.4%, 0.1 mol) prepared in step (1) to the reaction flask in eight portions, with a total addition time of 3 h. After addition, keep the reaction vessel warm for 4 h. After the reaction was complete, the solvent was removed under negative pressure. 120 mL of water was added to the residue in the reactor, and after stirring to dissolve, concentrated hydrochloric acid was added dropwise to acidify the pH of the system to 2. After filtration, rinsing with water, and drying, 32.5 g of product was obtained. HPLC quantification showed that the target compound 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid had a content of 98.0%, and the two-step reaction yield was 91.4% based on methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate.

[0094] Example 5

[0095] (1) The preparation of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate can be represented by the following reaction equation:

[0096]

[0097] Add 350 mL of tert-butanol to the reaction flask and start stirring. Add 6.9 g of potassium hydroxide (85%, 0.105 mol) dropwise at room temperature. After the potassium hydroxide is evenly dispersed, maintain the reactor temperature at 25 °C. Add 34.8 g of methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (98%, 0.1 mol) to the reactor for alkaline hydrolysis. The reaction is slightly exothermic; maintain the reactor temperature at 25 °C and react for 7 hours. After the reaction is complete, the normalized content of potassium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate is 98.3% as shown in the liquid chromatography. The solvent is removed under negative pressure and the solution is directly used for subsequent etherification.

[0098] (2) The preparation of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid can be represented by the following reaction equation:

[0099]

[0100] Add 150 mL of trifluoroethanol to the reaction vessel, start stirring, add 20 g of potassium hydride (30%, 0.15 mol) at room temperature, stir until completely dissolved, and obtain potassium trifluoroethanol alkoxide solid after solvent removal, and seal for later use.

[0101] 200 mL of THF was added to potassium trifluoroethanol, stirred and dissolved, and the temperature of the reactor was controlled at 5 °C. The potassium salt of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (98.3%, 0.1 mol) prepared in step (1) was added to the reaction flask in eight portions, with a total addition time of 3 h. After the addition was completed, the reaction was kept at the temperature for 3 h. After the reaction was completed, the product was desoluble under negative pressure. 120 mL of water was added to the reactor residue, stirred and dissolved, and concentrated hydrochloric acid was added dropwise to acidify the pH of the system to 2. After filtration, rinsing with water, and drying, 33.0 g of product was obtained. HPLC quantification showed that the content of the target compound 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid was 98.2%, and the yield of the two-step reaction was 93.5% based on methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate.

[0102] Example 6

[0103] (1) The preparation of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate can be represented by the following reaction equation:

[0104]

[0105] Add 350 mL of tert-butanol to the reaction flask and start stirring. Add 6.6 g of potassium hydroxide (85%, 0.1 mol) dropwise at room temperature. After the potassium hydroxide is evenly dispersed, maintain the reactor temperature at 25 °C. Add 34.8 g of methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (98%, 0.1 mol) to the reactor for alkaline hydrolysis. The reaction is slightly exothermic. Maintain the reactor temperature at 25 °C and react for 7 hours. After the reaction is complete, the normalized content of potassium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate is 97.3% as shown in the liquid chromatography. The solvent is removed under negative pressure and the solution is directly used for subsequent etherification reactions.

[0106] (2) The preparation of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid can be represented by the following reaction equation:

[0107]

[0108] Add 70 mL of LDM, 12.6 g of trifluoroethanol (99%, 0.125 mol), and 26.1 g of potassium hydroxide solution (30%, 0.14 mol) to the reaction vessel, start stirring, and control the temperature of the vessel at 5 °C. Add the potassium salt of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (97.3%, 0.1 mol) prepared in step (1) to the reaction flask in eight portions, with a total addition time of 2 h. After addition, keep the reaction vessel warm for 4 h. After the reaction was complete, the solvent was removed under negative pressure. 120 mL of water was added to the residue in the reactor, and after stirring to dissolve, concentrated hydrochloric acid was added dropwise to acidify the pH of the system to 2. After filtration, washing with water, and drying, 32.4 g of product was obtained. HPLC quantification showed that the target compound 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid had a content of 96.0%, and the two-step reaction yield was 89.3% based on methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate.

[0109] Example 7

[0110] (1) The preparation of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate can be represented by the following reaction equation:

[0111]

[0112] Add 200 mL of tert-butanol to the reaction flask and start stirring. Add 10.3 g of sodium tert-butoxide (98%, 0.105 mol) dropwise at room temperature. After the sodium tert-butoxide is evenly dispersed, maintain the reactor temperature at 25 °C. Add 34.8 g of methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (98%, 0.1 mol) to the reactor for alkaline hydrolysis. The reaction is slightly exothermic; maintain the reactor temperature at 25 °C and react for 6 hours. After the reaction is complete, the normalized content of sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate is 98.3% as shown in the liquid chromatography. The solvent is removed under negative pressure and the solution is directly used for subsequent etherification reactions.

[0113] (2) The preparation of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid can be represented by the following reaction equation:

[0114]

[0115] Add 130 mL THF, 10.6 g trifluoroethanol (99%, 0.105 mol) and 11.8 g sodium tert-butoxide (98%, 0.12 mol) to the reaction vessel, start stirring, control the vessel temperature at 10 °C, add the sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (98.3%, 0.1 mol) prepared in step (1) to the reaction flask in eight portions, with a total addition time of 3 h, and keep the reaction at the temperature for 4 h after addition. After the reaction was complete, the solvent was removed under negative pressure. 120 mL of water was added to the residue in the reactor, and after stirring to dissolve, concentrated hydrochloric acid was added dropwise to acidify the pH of the system to 2. After filtration, rinsing with water, and drying, 32.8 g of product was obtained. HPLC quantification showed that the target compound 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid had a content of 97.8%, and the two-step reaction yield was 92.7% based on methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate.

[0116] Example 8

[0117] (1) The preparation of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate can be represented by the following reaction equation:

[0118]

[0119] Add 200 mL of tert-butanol to the reaction flask and start stirring. Add 12.4 g of potassium tert-butoxide (95%, 0.105 mol) dropwise at room temperature. After the potassium tert-butoxide is evenly dispersed, maintain the reactor temperature at 25 °C. Add 34.8 g of methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (98%, 0.1 mol) to the reactor for alkaline hydrolysis. The reaction is slightly exothermic; maintain the reactor temperature at 25 °C and react for 6 hours. After the reaction is complete, the normalized content of potassium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate is 98.0% as shown in the liquid chromatography. The solvent is removed under negative pressure and the solution is directly used for subsequent etherification reactions.

[0120] (2) The preparation of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid can be represented by the following reaction equation:

[0121]

[0122] Add 100 mL of trifluoroethanol to the reaction vessel, start stirring, add 5.5 g of metallic potassium (99%, 0.14 mol) at room temperature, stir until completely dissolved, and obtain solid potassium trifluoroethanol after solvent removal, and seal for later use.

[0123] Add 130 mL of acetonitrile to potassium trifluoroethanol, stir to dissolve, and control the reactor temperature at 15 °C. Add the potassium salt of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (98.0%, 0.1 mol) prepared in step (1) to the reaction flask in eight portions, with a total addition time of 1 h. After addition, keep the reaction temperature constant for 6 h. After the reaction is complete, remove the solvent under negative pressure. Add 120 mL of water to the reactor residue, stir to dissolve, and then add concentrated hydrochloric acid dropwise to acidify the pH of the system to 3. After filtration, rinsing with water, and drying, 32.6 g of product is obtained. HPLC quantification shows that the content of the target compound 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid is 98.2%, and the two-step reaction yield is 91.9% based on methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate.

[0124] Example 9

[0125] (1) The preparation of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate can be represented by the following reaction equation:

[0126]

[0127] Add 200 mL of 2-methyl-2-pentanol to the reaction flask and start stirring. Add 4.2 g of sodium hydride (60%, 0.105 mol) dropwise at room temperature. After the sodium hydride is completely dissolved, maintain the reactor temperature at 25°C. Add 34.8 g of methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (98%, 0.1 mol) to the reactor for alkaline hydrolysis. The reaction is slightly exothermic. Maintain the reactor temperature at 25°C and react for 6 hours. After the reaction is complete, the normalized content of sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate is 97.8% as shown in the liquid chromatography. The solvent is removed under negative pressure and the solution is directly used for subsequent etherification reactions.

[0128] (2) The preparation of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid can be represented by the following reaction equation:

[0129]

[0130] Add 200 mL of DMF, 11.6 g of trifluoroethanol (99%, 0.115 mol), and 5.4 g of sodium hydroxide (96%, 0.13 mol) to the reaction vessel, start stirring, and control the vessel temperature at 5 °C. Add the sodium salt of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (97.8%, 0.1 mol) prepared in step (1) to the reaction flask in eight portions, with a total addition time of 3 h. After addition, keep the reaction temperature high for 6 h. After the reaction was complete, the solvent was removed under negative pressure. 120 mL of water was added to the residue in the reactor, and after stirring to dissolve, concentrated hydrochloric acid was added dropwise to acidify the pH of the system to 3. After filtration, washing with water, and drying, 32.4 g of product was obtained. HPLC quantification showed that the target compound 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid had a content of 96.5%, and the two-step reaction yield was 89.7% based on methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate.

[0131] Example 10

[0132] (1) The preparation of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate can be represented by the following reaction equation:

[0133]

[0134] Add 50 mL of tert-amyl alcohol and 150 mL of tert-butanol to the reaction flask, start stirring, and add 14.0 g of potassium hydride (30%, 0.105 mol) dropwise at room temperature. After the potassium hydride is completely dissolved, control the reactor temperature at 25°C, and add 34.8 g of methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (98%, 0.1 mol) to the reactor for alkaline hydrolysis. The reaction is slightly exothermic, and the reactor temperature is controlled at 25°C for 6 hours. After the reaction is complete, the normalized content of potassium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate is 98.2% as shown in the liquid chromatography. The solvent is removed under negative pressure and the product is directly used for subsequent etherification reactions.

[0135] (2) The preparation of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid can be represented by the following reaction equation:

[0136]

[0137] Add 200 mL of DMF, 13.6 g of trifluoroethanol (99%, 0.135 mol), and 9.9 g of potassium hydroxide (85%, 0.15 mol) to the reaction vessel, start stirring, and control the temperature of the vessel at 5 °C. Add the potassium salt of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (98.2%, 0.1 mol) prepared in step (1) to the reaction flask in eight portions, with a total addition time of 3 h. After addition, keep the reaction vessel warm for 5 h. After the reaction was complete, the solvent was removed under negative pressure. 120 mL of water was added to the residue in the reactor, and after stirring to dissolve, concentrated hydrochloric acid was added dropwise to acidify the pH of the system to 3. After filtration, washing with water, and drying, 32.5 g of product was obtained. HPLC quantification showed that the target compound 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid had a content of 97.1%, and the two-step reaction yield was 91.1% based on methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate.

[0138] Example 11

[0139] (1) The preparation of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate can be represented by the following reaction equation:

[0140]

[0141] Add 200 mL of tert-butanol to the reaction flask and start stirring. Add 2.4 g of 99% sodium metal (0.105 mol) at room temperature. After the sodium metal is completely dissolved, maintain the reactor temperature at 25°C. Add 34.8 g of methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (0.1 mol) to the reactor for alkaline hydrolysis. The reaction is slightly exothermic. Maintain the reactor temperature at 25°C and react for 6 hours. After the reaction is complete, the normalized content of sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate is 98.3% as shown in the liquid chromatography. The solvent is removed under negative pressure and the solution is directly used for subsequent etherification reactions.

[0142] (2) The preparation of 2-chloro-3-[(RS)-tetrahydrofuran-2-ylmethoxymethyl]-4-methanesulfonylbenzoic acid can be represented by the following reaction equation:

[0143]

[0144] Add 130 mL THF, 10.8 g 2-tetrahydrofuran methanol (99%, 0.105 mol) and 11.8 g sodium tert-butoxide (98%, 0.12 mol) to the reaction vessel, start stirring, control the vessel temperature at 10 °C, add the sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (98.3%, 0.1 mol) prepared in step (1) to the reaction flask in eight portions, with a total addition time of 3 h, and keep the reaction at the temperature for 4 h after addition. After the reaction was completed, the solvent was removed under negative pressure. 120 mL of water was added to the residue in the reactor, and after stirring to dissolve, concentrated hydrochloric acid was added dropwise to acidify the pH of the system to 3. After filtration, washing with water, and drying, 33.0 g of product was obtained. HPLC quantification showed that the target compound 2-chloro-3-[(RS)-tetrahydrofuran-2-ylmethoxymethyl]-4-methanesulfonylbenzoic acid had a content of 96.6%, and the two-step reaction yield was 91.4% based on methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate.

[0145] Example 12

[0146] (1) The preparation of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate can be represented by the following reaction equation:

[0147]

[0148] Add 200 mL of tert-butanol to the reaction flask and start stirring. Add 4.1 g of 99% potassium metal (0.105 mol) at room temperature. After the potassium metal is completely dissolved, maintain the reactor temperature at 25°C. Add 34.8 g of methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (0.1 mol) to the reactor for alkaline hydrolysis. The reaction is slightly exothermic. Maintain the reactor temperature at 25°C and react for 6 hours. After the reaction is complete, the normalized content of potassium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate is 98.1% as shown in the liquid chromatography. The solvent is removed under negative pressure and the solution is directly used for subsequent etherification reactions.

[0149] (2) The preparation of 2-chloro-3-[(RS)-tetrahydrofuran-2-ylmethoxymethyl]-4-methanesulfonylbenzoic acid can be represented by the following reaction equation:

[0150]

[0151] Add 130 mL of DMF, 10.8 g of 2-tetrahydrofuran methanol (99%, 0.105 mol) and 14.1 g of potassium tert-butoxide (95%, 0.12 mol) to the reaction vessel, start stirring, control the vessel temperature at 10 °C, add the potassium salt of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (98.1%, 0.1 mol) prepared in step (1) to the reaction flask in eight portions, with a total addition time of 3 h, and keep the reaction at the temperature for 4 h after addition. After the reaction was completed, the solvent was removed under negative pressure. 120 mL of water was added to the residue in the reactor, and after stirring to dissolve, concentrated hydrochloric acid was added dropwise to acidify the pH of the system to 3. After filtration, rinsing with water, and drying, 33.0 g of product was obtained. HPLC quantification showed that the target compound 2-chloro-3-[(RS)-tetrahydrofuran-2-ylmethoxymethyl]-4-methanesulfonylbenzoic acid had a content of 96.8%, and the two-step reaction yield was 91.8% based on methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate.

[0152] Example 13

[0153] (1) Following the same steps as described in Example 1, sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate with a content of 98.2% was obtained;

[0154] (2) The preparation of 2-chloro-3-[(RS)-tetrahydrofuran-2-ylmethoxymethyl]-4-methanesulfonylbenzoic acid can be represented by the following reaction equation:

[0155]

[0156] Add 200 mL of DMF, 11.8 g of 2-tetrahydrofuran methanol (99%, 0.115 mol) and 5.4 g of sodium hydroxide (96%, 0.13 mol) to the reaction vessel, start stirring, control the vessel temperature at 5 °C, add the sodium salt of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (98.2%, 0.1 mol) prepared in step (1) into the reaction flask in eight portions, with a total addition time of 3 h, and keep the reaction at the temperature for 6 h after addition. After the reaction was completed, the solvent was removed under negative pressure. 120 mL of water was added to the residue in the reactor, and after stirring to dissolve, concentrated hydrochloric acid was added dropwise to acidify the pH of the system to 3. After filtration, washing with water, and drying, 32.6 g of product was obtained. HPLC quantification showed that the target compound 2-chloro-3-[(RS)-tetrahydrofuran-2-ylmethoxymethyl]-4-methanesulfonylbenzoic acid had a content of 95.3%, and the two-step reaction yield was 89.1% based on methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate.

[0157] Example 14

[0158] (1) Following the same steps as described in Example 1, sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate with a content of 98.2% was obtained;

[0159] (2) The preparation of 2-chloro-3-[(RS)-tetrahydrofuran-2-ylmethoxymethyl]-4-methanesulfonylbenzoic acid can be represented by the following reaction equation:

[0160]

[0161] Add 200 mL of LDM, 11.8 g of 2-tetrahydrofuran methanol (99%, 0.115 mol), and 8.6 g of potassium hydroxide (85%, 0.13 mol) to the reaction vessel, start stirring, and control the vessel temperature at 5 °C. Add the sodium salt of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (98.2%, 0.1 mol) prepared in step (1) to the reaction flask in eight portions, with a total addition time of 3 h. After addition, keep the reaction temperature high for 5 h. After the reaction was completed, the solvent was removed under negative pressure. 120 mL of water was added to the residue in the reactor, and after stirring to dissolve, concentrated hydrochloric acid was added dropwise to acidify the pH of the system to 3. After filtration, rinsing with water, and drying, 32.6 g of product was obtained. HPLC quantification showed that the target compound 2-chloro-3-[(RS)-tetrahydrofuran-2-ylmethoxymethyl]-4-methanesulfonylbenzoic acid had a content of 95.9%, and the two-step reaction yield was 89.8% based on methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate.

[0162] Example 15

[0163] (1) Following the same steps as described in Example 1, sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate with a content of 98.2% was obtained;

[0164] (2) The preparation of 2-chloro-3-[(RS)-tetrahydrofuran-2-ylmethoxymethyl]-4-methanesulfonylbenzoic acid can be represented by the following reaction equation:

[0165]

[0166] Add 160 mL of LDM, 11.8 g of 2-tetrahydrofuran methanol (99%, 0.115 mol), and 17.3 g of sodium hydroxide solution (30%, 0.13 mol) to the reaction vessel, start stirring, and control the vessel temperature at 5 °C. Add the sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (98.2%, 0.1 mol) prepared in step (1) to the reaction flask in eight portions, with a total addition time of 2 h. After addition, keep the reaction temperature high for 4 h. After the reaction was completed, the solvent was removed under negative pressure. 120 mL of water was added to the residue in the reactor, and after stirring to dissolve, concentrated hydrochloric acid was added dropwise to acidify the pH of the system to 3. After filtration, rinsing with water, and drying, 32.6 g of product was obtained. HPLC quantification showed that the target compound 2-chloro-3-[(RS)-tetrahydrofuran-2-ylmethoxymethyl]-4-methanesulfonylbenzoic acid had a content of 94.6%, and the two-step reaction yield was 88.4% based on methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate.

[0167] Example 16

[0168] (1) Following the same steps as described in Example 1, sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate with a content of 98.2% was obtained;

[0169] (2) The preparation of 2-chloro-3-[(RS)-tetrahydrofuran-2-ylmethoxymethyl]-4-methanesulfonylbenzoic acid can be represented by the following reaction equation:

[0170]

[0171] Add 70 mL of LDM, 12.9 g of 2-tetrahydrofuran methanol (99%, 0.125 mol), and 26.1 g of potassium hydroxide solution (30%, 0.14 mol) to the reaction vessel, start stirring, and control the vessel temperature at 5 °C. Add the sodium salt of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (98.2%, 0.1 mol) prepared in step (1) to the reaction flask in eight portions, with a total addition time of 2 h. After addition, keep the reaction temperature high for 4 h. After the reaction was complete, the solvent was removed under negative pressure. 120 mL of water was added to the residue in the reactor, and after stirring to dissolve, concentrated hydrochloric acid was added dropwise to acidify the pH of the system to 2. After filtration, rinsing with water, and drying, 32.6 g of product was obtained. HPLC quantification showed that the target compound 2-chloro-3-[(RS)-tetrahydrofuran-2-ylmethoxymethyl]-4-methanesulfonylbenzoic acid had a content of 94.8%, and the two-step reaction yield was 88.8% based on methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate.

[0172] Example 17

[0173] (1) Following the same steps as described in Example 1, sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate with a content of 98.2% was obtained;

[0174] (2) The preparation of 2-chloro-3-[(RS)-tetrahydrofuran-2-ylmethoxymethyl]-4-methanesulfonylbenzoic acid can be represented by the following reaction equation:

[0175]

[0176] Add 50 mL of 2-tetrahydrofuran-methanol to the reaction vessel, start stirring, add 5.2 g of sodium hydride (60%, 0.13 mol) at room temperature, stir until completely dissolved, and obtain sodium 2-tetrahydrofuran-methanol solid by desolvation under negative pressure using a high vacuum oil pump, and seal for later use.

[0177] 200 mL of THF was added to sodium 2-tetrahydrofuranmethylol alcohol, stirred and dissolved, and the temperature of the vessel was controlled at 5 °C. Sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (98.2%, 0.1 mol) prepared in step (1) was added to the reaction flask in eight portions, with a total addition time of 3 h. After addition, the reaction was kept at the temperature for 3 h. After the reaction was completed, the product was desolvated under negative pressure. 120 mL of water was added to the residue in the vessel, stirred and dissolved, and concentrated hydrochloric acid was added dropwise to acidify the pH of the system to 3. After filtration, rinsing with water, and drying, 33.1 g of product was obtained. HPLC quantification showed that the content of the target compound 2-chloro-3-[(RS)-tetrahydrofuran-2-ylmethoxymethyl]-4-methanesulfonylbenzoic acid was 97.5%, and the yield of the two-step reaction was 92.5% based on methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate.

[0178] Example 18

[0179] (1) Following the same steps as described in Example 1, sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate with a content of 98.2% was obtained;

[0180] (2) The preparation of 2-chloro-3-[(RS)-tetrahydrofuran-2-ylmethoxymethyl]-4-methanesulfonylbenzoic acid can be represented by the following reaction equation:

[0181]

[0182] Add 150 mL of 2-tetrahydrofuran-methanol to the reaction vessel, start stirring, add 20 g of potassium hydride (30%, 0.15 mol) at room temperature, stir until completely dissolved, and obtain solid 2-tetrahydrofuran-methanol potassium alkoxide after desolvation under negative pressure using a high vacuum oil pump, and seal for later use.

[0183] 200 mL of THF was added to potassium 2-tetrahydrofuran-methanol, stirred and dissolved, and the temperature of the reactor was controlled at 5 °C. Sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (98.2%, 0.1 mol) prepared in step (1) was added to the reaction flask in eight portions, with a total addition time of 3 h. After addition, the reaction was kept at the temperature for 3 h. After the reaction was completed, the solution was removed under negative pressure, and 120 mL of water was added to the reactor residue. After stirring and dissolving, concentrated hydrochloric acid was added dropwise to acidify the pH of the system to 3. After filtration, rinsing with water, and drying, 33.1 g of product was obtained. HPLC quantification showed that the content of the target compound 2-chloro-3-[(RS)-tetrahydrofuran-2-ylmethoxymethyl]-4-methanesulfonylbenzoic acid was 97.0%, and the yield of the two-step reaction was 92.2% based on methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate.

[0184] Example 19

[0185] (1) Following the same steps as described in Example 1, sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate with a content of 98.2% was obtained;

[0186] (2) The preparation of 2-chloro-3-[(RS)-tetrahydrofuran-2-ylmethoxymethyl]-4-methanesulfonylbenzoic acid can be represented by the following reaction equation:

[0187]

[0188] Add 50 mL of 2-tetrahydrofuran-methanol to the reaction vessel, start stirring, add 2.8 g of metallic sodium (99%, 0.12 mol) at room temperature, stir until completely dissolved, and obtain solid 2-tetrahydrofuran-methanol sodium alkoxide after desolvation under negative pressure using a high vacuum oil pump, and seal for later use.

[0189] 70 mL of DMSO was added to sodium 2-tetrahydrofuranmethylol alcohol, stirred and dissolved, and the temperature of the reactor was controlled at -5 °C. Sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (98.2%, 0.1 mol) prepared in step (1) was added to the reaction flask in eight portions, with a total addition time of 2 h. After addition, the reaction was kept at the temperature for 5 h. After the reaction was completed, the solution was removed under negative pressure, and 120 mL of water was added to the reactor residue. After stirring and dissolving, concentrated hydrochloric acid was added dropwise to acidify the pH of the system to 3. After filtration, water rinsing and drying, 33.4 g of product was obtained. HPLC quantification showed that the content of the target compound 2-chloro-3-[(RS)-tetrahydrofuran-2-ylmethoxymethyl]-4-methanesulfonylbenzoic acid was 95.5%, and the yield of the two-step reaction was 91.5% based on methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate.

[0190] Example 20

[0191] (1) Following the same steps as described in Example 1, sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate with a content of 98.2% was obtained;

[0192] (2) The preparation of 2-chloro-3-[(RS)-tetrahydrofuran-2-ylmethoxymethyl]-4-methanesulfonylbenzoic acid can be represented by the following reaction equation:

[0193]

[0194] Add 100 mL of 2-tetrahydrofuran-methanol to the reaction vessel, start stirring, add 5.5 g of metallic potassium (99%, 0.14 mol) at room temperature, stir until completely dissolved, and obtain solid 2-tetrahydrofuran-methanol potassium alkoxide after desolvation under negative pressure using a high vacuum oil pump, and seal for later use.

[0195] Add 130 mL of acetonitrile to potassium 2-tetrahydrofuran-methanol, stir to dissolve, and control the temperature of the vessel at 15 °C. Add the sodium salt of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate (98.2%, 0.1 mol) prepared in step (1) to the reaction flask in eight portions, with a total addition time of 1 h. After addition, keep the reaction temperature high for 6 h. After the reaction is complete, remove the solvent under negative pressure. Add 120 mL of water to the vessel residue, stir to dissolve, and then add concentrated hydrochloric acid dropwise to acidify the pH of the system to 2. After filtration, rinsing with water, and drying, 32.6 g of product is obtained. HPLC quantification shows that the content of the target compound 2-chloro-3-[(RS)-tetrahydrofuran-2-ylmethoxymethyl]-4-methanesulfonylbenzoic acid is 97.0%, and the yield of the two-step reaction is 90.8% based on methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate.

[0196] The applicant declares that this invention illustrates the preparation method of 2-chloro-3-alkoxymethyl-4-methanesulfonylbenzoic acid through the above embodiments, specifically referring to the preparation methods of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid and 2-chloro-3-[(RS)-tetrahydrofuran-2-ylmethoxymethyl]-4-methanesulfonylbenzoic acid. However, this invention is not limited to the detailed methods described above, that is, it does not mean that this invention must rely on the detailed methods described above to be implemented. Those skilled in the art should understand that any improvements to this invention, equivalent substitutions of the raw materials for the product of this invention, additions of auxiliary components, and selection of specific methods all fall within the protection and disclosure scope of this invention.

Claims

1. A process for the preparation of 2-chloro-3-alkoxymethyl-4- methanesulfonylbenzoic acid, characterized in that, The steps include the following: (1) Methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate was subjected to esterification in a tertiary alcohol solvent in the presence of an alkaline substance to obtain 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate; (2) 2-Chloro-3-bromomethyl-4-methanesulfonylbenzoate is reacted with an alcohol in the presence of an alkaline substance or 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate is reacted with an alkali metal alkoxide to obtain the 2-chloro-3-alkoxymethyl-4-methanesulfonylbenzoic acid; The tertiary alcohol mentioned in step (1) is any one or a combination of at least two of tert-butanol, tert-amyl alcohol, or 2-methyl-2-pentanol; In step (1), the amount of the tertiary alcohol solvent used is 700 to 3500 mL relative to 1 mol of methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate; In step (2), when the 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate reacts with an alcohol in the presence of an alkaline substance, the order of addition is to first add the alkaline substance and the alcohol to the reaction solvent, and then add the 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate. In step (2), the reaction sequence of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate with alkali metal alkoxide is as follows: first, the alkali metal alkoxide is placed in the solvent, and then the 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate is added.

2. The production method according to claim 1, characterized by, The tertiary alcohol mentioned in step (1) is tert-butanol.

3. The preparation method according to claim 1, characterized in that, The molar ratio of methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate to the alkaline substance in step (1) is 1:(1 to 1.1).

4. The production method according to claim 1, characterized by, The alkaline substance mentioned in step (1) is any one of sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, potassium hydride, metallic sodium, or metallic potassium.

5. The preparation method according to claim 4, characterized in that, The alkaline substance mentioned in step (1) is sodium hydroxide.

6. The preparation method according to claim 4, characterized in that, The mass concentration of the sodium hydroxide is 30-96%.

7. The preparation method according to claim 4, characterized in that, The mass concentration of the potassium hydroxide is 30-96%.

8. The method of claim 1, wherein, The temperature of the esterification reaction in step (1) is 25–40 °C.

9. The method of claim 1, wherein, The esterification reaction in step (1) takes 5 to 12 hours.

10. The method of claim 1, wherein, The alcohol mentioned in step (2) is 2,2,2-trifluoroethanol or 2-tetrahydrofuran methanol.

11. The method of claim 1, wherein, The molar ratio of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate to alcohol in step (2) is 1:(1.05-1.35).

12. The method of claim 1, wherein, The alkaline substance mentioned in step (2) is any one of sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, and potassium hydride.

13. The method of claim 12, wherein, The mass concentration of the sodium hydroxide is 30-96%.

14. The method of claim 12, wherein, The mass concentration of the potassium hydroxide is 30-96%.

15. The method of claim 1, wherein, The molar ratio of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate to the alkaline substance in step (2) is 1:(1.2 to 1.5).

16. The method of claim 1, wherein, The molar ratio of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate to alkali metal alkoxide in step (2) is 1:(1.2-1.5).

17. The method of claim 1, wherein, The alkali metal alkoxide mentioned in step (2) is obtained by reacting an alcohol with an alkali metal.

18. The method of claim 17, wherein, The alkali metal is sodium or potassium.

19. The method of claim 1, wherein, The solvent used in step (2) is any one or a combination of at least two of acetonitrile, DMF, DMSO or THF.

20. The method of claim 1, wherein, In step (2), the amount of solvent used is 700 to 3500 mL relative to 1 mol of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate.

21. The method of claim 1, wherein, After the reaction in step (2) is completed, acidification is performed to obtain the 2-chloro-3-alkoxymethyl-4-methanesulfonylbenzoic acid.

22. The method of claim 21, wherein, The acid used in the acidification is hydrochloric acid.

23. The preparation method according to claim 21, characterized in that, The pH value of the acidified reaction system is 2 to 3.

24. The method of claim 1, wherein, The reaction temperature in step (2) is -5 to 15°C.

25. The method of claim 1, wherein, The 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate in step (2) is added to the reaction system in step (2) in batches, and the total feeding time of the 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate is 1 to 3 hours.

26. The method of claim 1, wherein, The reaction time in step (2) is 3 to 6 hours.

27. The method of claim 1, wherein, The steps include the following: (1) Methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate is subjected to esterification in a tertiary alcohol solvent in the presence of an alkaline substance for 5-12 h at 25-40 °C to obtain 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate. The amount of the tertiary alcohol solvent used is 700-3500 mL relative to 1 mol of the methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate, and the molar ratio of the methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate to the alkaline substance is 1:(1-1.1). (2) 2-Chloro-3-bromomethyl-4-methanesulfonylbenzoate is reacted with an alcohol in the presence of an alkaline substance, or 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate is reacted with an alkali metal alkoxide, wherein the molar ratio of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate to alcohol is 1:(1.05~1.35), the molar ratio of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate to alkaline metal alkoxide is 1:(1.2~1.5), the molar ratio of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate to alkali metal alkoxide is 1:(1.2~1.5), the reaction time is 3~6h, the reaction temperature is -5~15℃, and the 2-chloro-3-alkoxymethyl-4-methanesulfonylbenzoic acid is obtained after solvent removal, water dilution, acidification, filtration and drying; The tertiary alcohol mentioned in step (1) is any one or a combination of at least two of tert-butanol, tert-amyl alcohol, or 2-methyl-2-pentanol.

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